Intranasal deferoxamine reverses iron-induced memory deficits and inhibits amyloidogenic APP processing in a transgenic mouse model of Alzheimer's disease

Increasing evidence indicates that a disturbance of normal iron homeostasis and an amyloid-beta (A beta)-iron interaction may contribute to the pathology of Alzheimer's disease (AD), whereas iron chelation could be an effective therapeutic intervention. In the present study, transgenic mice expressing amyloid precursor protein (APP) and presenilin 1 and watered with high-dose iron served as a model of AD. We evaluated the effects of intranasal administration of the high-affinity iron chelator deferoxamine (DFO) on A beta neuropathology and spatial learning and memory deficits created in this AD model. The effects of Fe, DFO, and combined treatments were also evaluated in vitro using SHSY-5Y cells overexpressing the human APP Swedish mutation. In vivo, no significant differences in the brain concentrations of iron, copper, or zinc were found among the treatment groups. We found that high-dose iron (deionized water containing 10 mg/mL FeCl3) administered to transgenic mice increased protein expression and phosphorylation of APP695, enhanced amyloidogenic APP cleavage and A beta deposition, and impaired spatial learning and memory. Chelation of iron via intranasal administration of DFO (200 mg/kg once every other day for 90 days) inhibited iron-induced amyloidogenic APP processing and reversed behavioral alterations. DFO treatment reduced the expression and phosphorylation of APP protein by shifting the processing of APP to the nonamyloidogenic pathway, and the reduction was accompanied by attenuating the A beta burden, and then significantly promoted memory retention in APP/PS1 mice. The effects of DFO on iron-induced amyloidogenic APP cleavage were further confirmed in vitro. Collectively, the present data suggest that intranasal DFO treatment may be useful in AD, and amelioration of iron homeostasis is a potential strategy for prevention and treatment of this disease. (C) 2013 Elsevier Inc. All rights reserved.